MENOPAUSE, GENES AND METABOLISM AFTER WEIGHT LOSS AND EXERCISE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The prevalence of obesity continues to rise in the U.S. with estimates that 1/3 of the population is overweight. The incidence of obesity is 49% in African-American women compared to 33% in Caucasian women. Moreover, African-American women are significantly more insulin resistant and have twice the prevalence of type 2 diabetes than Caucasians. The reasons for these racial disparities are not entirely explained by differences in obesity. The hypotheses are that there are ethnic (African American vs. Caucasian) and genetic differences in the mechanisms and magnitude by which hypocaloric weight loss (WL) and aerobic exercise (AEX) affect body composition, glucose, lipid, muscle and adipose tissue metabolism in overweight, insulin resistant postmenopausal women. This will be tested in a trial comparing the effects of WL vs. AEX+WL on glucose, lipid, fat and muscle metabolism in overweight African American and Caucasian postmenopausal women with the following specific aims: 1. To determine whether there are racial (African American vs. Caucasian) and/or genetic differences in the effects of WL vs. AEX+WL on the metabolic actions of insulin on glucose, muscle, and fat metabolism by measuring insulin sensitivity, free fatty acid (FFA) suppression and insulin signaling proteins and activities in muscle biopsies during hyperinsulinemic-euglycemic clamps before and after the interventions. 2. To determine the cellular mechanisms by which the addition of AEX to WL affects insulin sensitivity in African American compared to Caucasian women by ascertaining the effects of WL vs. AEX+WL on proteins affecting insulin action (such as GLUT4, IRS1 and PI-3 kinase) in skeletal muscle (including micro-array technology), and insulin suppression of lipolysis in isolated adipocytes. 3. To determine whether there are racial differences in the skeletal muscle and adipose tissue metabolic responses to weight loss and exercise, and the changes in body composition, lipids and insulin sensitivity. 4. To determine whether genetic variation in the lipoprotein lipase (LPL) PvuII gene and/or other obesity-diabetes gene polymorphisms affect fasting LPL activity in muscle and adipose tissue and the metabolic responses to a hypocaloric diet, to alter the magnitude of the reduction in total and visceral fat, and glucose/insulin and lipoprotein lipids during longterm dietary-induced WL in obese postmenopausal women. 5. To determine in exploratory analyses if there are gene-race-environment interactions which affect insulin sensitivity and the response to weight loss and aerobic exercise or weight loss alone in African-American and Caucasian women.